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Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel.

Författare och institution:
Martin Lidell (Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik); Darcy M Moncada (-); Kris Chadee (-); Gunnar C. Hansson (Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi)
Publicerad i:
Proceedings of the National Academy of Sciences of the United States of America, 103 ( 24 ) s. 9298-303
Artikel, refereegranskad vetenskaplig
Sammanfattning (abstract):
In order for the protozoan parasite Entamoeba histolytica (E.h.) to cause invasive intestinal and extraintestinal infection, which leads to significant morbidity and mortality, it must disrupt the protective mucus layer by a previously unknown mechanism. We hypothesized that cysteine proteases secreted from the amoeba disrupt the mucin polymeric network, thereby overcoming the protective mucus barrier. The MUC2 mucin is the major structural component of the colonic mucus gel. Heavily O-glycosylated and protease-resistant mucin domains characterize gel-forming mucins. Their N- and C-terminal cysteine-rich domains are involved in mucin polymerization, and these domains are likely to be targeted by proteases because they are less glycosylated, thereby exposing their peptide chains. By treating recombinant cysteine-rich domains of MUC2 with proteases from E.h. trophozoites, we showed that the C-terminal domain was specifically targeted at two sites by cysteine proteases, whereas the N-terminal domain was resistant to proteolysis. The major cleavage site is predicted to depolymerize the MUC2 polymers, thereby disrupting the protective mucus gel. The ability of the cysteine proteases to dissolve mucus gels was confirmed by treating mucins from a MUC2-producing cell line with amoeba proteases. These findings suggest a major role for E.h. cysteine proteases in overcoming the protective mucus barrier in the pathogenesis of invasive amoebiasis. In this report, we identify a specific cleavage mechanism used by an enteric pathogen to disrupt the polymeric nature of the mucin gel.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Animals, CHO Cells, Colon, anatomy & histology, parasitology, Cricetinae, Cysteine Endopeptidases, genetics, metabolism, Entamoeba histolytica, enzymology, pathogenicity, Humans, Intestinal Mucosa, chemistry, metabolism, parasitology, Mucins, chemistry, genetics, metabolism, Mucus, metabolism, Mutation, Protein Structure, Tertiary, Protozoan Proteins, genetics, metabolism
Postens nummer:
Posten skapad:
2007-11-08 16:14
Posten ändrad:
2011-01-20 09:59

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